A scintillating opening 15 minutes that yielded two goals from striker Marquinhos and defender Egidio on Sunday extended Cruzeiro's lead at the summit to five points.
Defending champions Cruzeiro hit the front through Marquinhos after just five minutes, with the Brazilian forward winning the ball on the edge of the area before surging towards goal and firing past Botafogo goalkeeper Jefferson.
Egidio doubled the home side's lead 11 minutes later, curling a free-kick into the top corner of the net as Jefferson stood helpless on his line.
Botafogo managed to pull a goal back in the first minute of injury time, albeit fortuitously after Cruzeiro defender Leo sent the ball past his own keeper, but it did not affect the result.
Cruzeiro are on track for their fourth Serie A crown with six rounds remaining, while Botafogo are one point adrift of safety and facing relegation to Brazil's second tier.
Sao Paulo continue to remain hot on the heels of Cruzeiro following their late 2-1 win at cellar-dwelling Criciuma on the same day.
Defender Edson Silva headed Sao Paulo into a 37th-minute lead, converting Michel Bastos' corner.
But Criciuma, who languish four points from safety, got back on level terms via Souza with 19 minutes left.
Criciuma's joy was short-lived, however, as Alan Kardec rose highest to head the ball powerfully into the ground and into the top of the net seven minutes from time.
Sao Paulo are five points behind Cruzeiro and three clear of International, who were also winners on Sunday.
Charles Aranguiz scored twice as International prevailed 2-1 against eighth-placed Santos.
Fluminense (54 points, plus 20 goal difference) replaced Atletico Mineiro (54 points, plus 9) in the qualifying position for the Copa Libertadores first stage with victory over Goias on Saturday.
Goals to former Brazil international Fred and Dario Conca helped Fluminense to a 2-0 win, which was enough to claim fourth spot on goal difference after Mineiro lost 1-0 at Atletico Paranaense on Sunday.
Gremio and Corinthians are also level on 54 points.
A Richarlyson own goal gave Gremio a 1-0 triumph against 16th-placed Vitoria, while Corinthians rallied from two goals down to draw 2-2 with fourth-bottom Coritiba.
In other results, Nixon's double inspired Flamengo to a 3-0 win at the expense of Chapecoense.
Palmeiras were 1-0 winners over second-bottom Bahia, while Sport Recife edged Figueirense by the same scoreline.
